Impact/Purpose:

Research in this area is aimed at providing methods, data, and models to enable EPA to reduce uncertainty in risk assessments of acute, chronic, and multipathway exposures to air toxics at the national and regional levels. Research also is focused on conducting community-level exposure assessments and epidemiology studies to characterize the risk of air toxics at the local scale. This work will significantly advance the scientific understanding of the acute neurotoxicity of volatile organic compounds (VOCs). If successful, this work will fill out an EDR model that will quantitatively link VOC exposure to adverse functional effects in the whole live animal by describing (1) the relationship between exposure scenario and internal dose via PBPK models; (2) the mode of action in the CNS by pharmacologically-defined neurotransmitter mediation of adverse functional effects in vivo; and (3) specific changes in neural receptor function in vitro. This model will thereby yield a valuable conceptual tool for understanding the events that link VOC exposure to acute adverse effects mediated by the CNS, by accounting for dosimetric and mechanistic events that mediate the those effects.

Description:

SUMMARY: The major accomplishment of NTD’s air toxics program is the development of an exposure-dose- response model for acute exposure to volatile organic compounds (VOCs), based on momentary brain concentration as the dose metric associated with acute neurological impairments. This is one of the few cases in which pharmacokinetic analysis has been applied quantitatively to describe a neurotoxic event. This project has focused on the neurotoxic effects of VOCs such as trichloroethylene and toluene, which make up a major portion of the high-volume air toxics compounds that EPA must regulate. The significance of this accomplishment is illustrated by application to risk assessment issues such as extrapolation across exposure durations and across species for recommending Acute Exposure Guideline Level (AEGL) values to the National Research Council (NRC). Another significant application of these models is estimation of the monetary value of neurological impairments avoided in proposed regulations. Further work will include application of mode-of-action information to the acute model and development of a model of subchronic exposure. APPROACH: We hypothesize that the acute neurotoxicity of toluene is mediated at least in part by inhibition of nicotinic acetylcholine receptors (nAChRs), and that enhancement of nAChR function represents a common mode of action for the acute neurotoxicity of many VOCs. Specifically, we hypothesize that VOC induced changes in sensitivity of these receptors mediates (a) reduced amplitude of visual evoked potentials and (b) reduced accuracy and increased latency of responding in signal detection tests. We propose to develop an in vitro model of the acute neurotoxicity of VOCs based upon their interactions with these receptors, and to link these interactions at the receptor level with sensory (visual evoked potentials) and cognitive (signal detection) effects in the live animal. If the effects of VOCs in vivo can be predicted by tests in vitro, the in vitro model will then be used to screen other VOCs for their effects on neuronal receptor function, thus permitting classification of VOCs according to their acute neurotoxicity. The in vitro test could also be used to study the effects of mixtures. If an NAChR model partially predicts functional effects of VOCs, future studies will assess the roles of NMDA voltage-gated calcium channels and GABA-A receptors. This work has used toluene as a model VOC because of an extensive database for this VOC in humans and other animals. Once defined for toluene, the mechanisms involved in the acute effects of other VOCs will be studied by these methods as well.

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